In submitting this NIH Mentored Research Scientist Development Award, my overarching goal is to become an independent investigator focused on developing and testing feasible, effective interventions to prevent tuberculosis (TB) in children i resource-limited settings. This field of inquiry is critically important given the unprecedented hih pediatric TB rates in countries with high HIV prevalence and the limited availability of interventions to reduce the TB burden among children. Although TB is curable and preventable, studies have demonstrated higher mortality and morbidity in young children, particularly in HIV-infected children, highlighting the importance of preventing TB in this population. Effective interventions to inform policy and program design are urgently needed so that TB can be prevented in this population in high HIV/TB-burden, resource-limited settings. My long-term career goal is to apply acquired knowledge and experience from pediatric TB research to other infectious diseases and ultimately other conditions that affect children and threaten their well-being. The purpose of this K01 application is to propose a research and training program that will facilitate attainment of these goals. My immediate goal is to develop and test an intervention to reduce childhood TB in Lesotho, a small country in southern Africa with a substantial TB/HIV disease burden. As with many resource-limited countries, particularly in sub-Saharan Africa, there is limited implementation of proven tracing, screening, and treatment strategies for child contacts of adult TB in Lesotho. The proposed study will be situated within ICAP's established Lesotho programs, which aim to strengthen TB/HIV integration at national, district, facility, and community levels and which are led by co-mentor Dr. Andrea Howard. Using ICAP's extensive Lesotho infrastructure will enable me to lead and conduct this vital study in a timely, cost-effective manner and, most importantly, in partnership with TB control entities in-country. The study will utilize a two-arm cluster randomized trial design, randomized at health facility level, o evaluate the effectiveness and acceptability of a community-based intervention (CBI) versus standard of care (SOC) to identify child contacts of adult TB cases in Mafeteng, Lesotho, and provide them with isoniazid preventive therapy (IPT), as indicated. Ten health centers will be included in the study and randomized to deliver the CBI or SOC, with stratification by facility siz (i.e., number of registered TB patients). CBI includes structural, clinical, and psychosocial components to address the challenges faced by healthcare workers (HCW), children, and guardians in provision of IPT for child contacts. At CBI sites, HCW and village health workers (VHW) will be trained to deliver study components to adult TB cases and their child contacts. SOC sites will follow country guidelines for contact tracing, screening, and IPT provision. CBI includes 3 components to maximize effect: 1) provider training on active community contact tracing, evaluating child contacts for IPT eligibility, and IPT provision; 2) specific intervention for children and guardians on the importance of child screening, initiating and completing IPT, and HIV testing and linkage to care for HIV-infected children; and 3) community outreach teams of VHW working in concert with facility-based teams. The study will have a strong qualitative research component, which includes pre- and post-intervention focus group discussions and post-intervention guardian key informant interviews. Using a sequential explanatory phase, where quantitative data collection and analysis is followed by collection and analysis of qualitative data that may help explain previous-phase results, will permit evaluation of provider and guardian acceptability and utilization of intervention components. My research and complementary training plan will allow me to acquire the skills and knowledge to become a productive, independent investigator able to design and evaluate interventions to prevent TB in children in high TB/HIV-burden, resource-limited settings. Effective, evidence-based interventions to prevent childhood TB in such settings are urgently needed. In the proposed study, innovative methodology will assess effectiveness and acceptability of a CBI that holistically addresses the complex provider-, patient-, and guardian-related barriers to prevention of childhood TB. It is anticipated that using a feasible community-based model of care will improve TB prevention in young, vulnerable children. The study will provide evidence for the feasible implementation and scale-up of IPT provision in children while integrating much-needed TB and HIV services in children.